Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation

Abstract

The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

Figure 1.

Distribution of donor-specific anti-HLA antibodies in kidney transplant recipients. rCXM+, patients with positive remote CDCXM; rCXM−, patients with negative remote CDCXM; peak HLA-DSA Luminex+, patients with donor-specific HLA antibodies detected by SAFB Luminex technique on the peak sera; peak HLA-DSA Luminex−, patients without donor-specific HLA antibodies detected by SAFB Luminex technique on the peak sera.

Figure 2.

The presence of HLA-DSAs on the highest rank pregraft serum associates with a significantly decreased graft survival (A), regardless of whether HLA-DSAs were class I or II (B). (C) The occurrence of acute AMR associates with a significantly decreased graft outcome. (D) Even in the absence of acute AMR, patients with preexisting HLA-DSAs have poorer graft survival as compared to patients without preexisting HLA-DSAs. Donor-specific HLA antibodies are detected by SAFB Luminex technique. P values are calculated with the use of the log-rank test.

Figure 3.

Peak HLA-DSA MFIs are better predictors of acute AMR than current HLA-DSA MFIs. Peak versus current ROC AUC was compared using χ² test with Bonferroni correction.

Figure 4.

The graft survival in patients with preexisting HLA-DSA MFIs >3000 is significantly lower than in patients with HLA-DSA MFIs ≤3000. Kaplan-Meier estimates of graft survival according to the MFI_max of preexisting HLA-DSAs in the entire cohort of kidney transplant patients (A) and in the subgroup of patients without acute AMR (B).